1. Field of the Invention
The present invention relates to anti-cancer drugs and, more particularly, to a method for inhibiting prostate cancer by kinases and angiogenesis inhibitory mechanisms of a class of cycloartanes extracted from Ball Moss (Tillandsia Recurvata).
2. Description of the Background
There is great growth in the overlapping fields of biology, technology, and medicine, including remarkable advances in cellular biology that have given a new understanding of the molecular basis for some diseases. Nevertheless, the incidence of some forms of cancer continues to rise. This is particularly true of prostate cancer, a leading cause of death in men. Indeed, prostate cancer is the second most frequently diagnosed cancer and sixth leading cause of cancer death in males worldwide. A. Jemal et al., Global Cancer Statistics, Ca Cancer J Clin 2011;61:69-90 (March-April 2011).
The three conventional treatment options include surgery, radiation and chemotherapy, or some combination of the three. Chemotherapy is the most widely used tool in prostate cancer treatment especially where the cancer has metastasized or spread to other organs of the body. However, conventional chemotherapy is not specific to cancer cells and has serious toxic side effects. Moreover, in recent years prostate cancer cells have exhibited increased resistance to current chemotherapies. Consequently, there exists an urgent need to discover and develop new therapeutics that can slow the growth of cancer cells while having lesser side effects on the patients. The search for new molecules to combat the rising cases of prostate cancer especially those resistant to current chemotherapy calls for urgent action.
The more recent development of target therapies for the treatment of human cancers is revolutionizing the concept of cancer treatment today and has led to a profusion of drugs to treat cancer patients. These drugs include alkylating agents, intercalating agents, antimetabolites, etc., most of which target DNA or enzymes regulating the DNA duplication and elongation process. However, rapidly growing tumors do not always exhibit high levels of cell proliferation, but may also exhibit low levels of cell death compared to the normal cell population from which these tumor cells issue. For these types of rapidly growing tumors, the mentioned drugs are not effective. In addition, like chemotherapy, the great majority of the drugs currently available for treatment of cancer are toxic and involve detrimental side-effects on healthy cells, tissues and organs. Targeted anticancer therapies rely on compounds that interfere with cellular targets, e.g., they inhibit molecular targets that play a pivotal rote in tumor progression. Such therapies specifically target the cancer cells, thus minimizing toxicity. A number of such target-based anticancer therapies are now successfully used in routine clinical practice.
A kinase is an enzyme that activates or inactivates certain proteins that control several biological activities in the cell including cell growth, proliferation, apoptosis (programmed cell death) and metabolism. There are two main types of kinases: those that phosphorylate tyrosine residues and those that phosphorylate serine and/or threonine residues in target proteins. The latter, protein kinase inhibitor's, may be categorized by the amino acids whose phosphorylation is inhibited. The body uses kinases extensively to transmit signals and control complex processes in cells, and myriad different kinases have been identified in humans. In the event of carcinogenesis, eukaryotic cells become predisposed to rapid and uncontrollable growth. This is evidenced by elevated levels of different kinases expressed in various cancers. It is for this reason that kinase inhibitors hold promise in restoring normal cell proliferation and may provide a key cancer treatment. Consequently, in recent years kinase inhibitors have emerged as major targets for therapeutics, particularly for cancer related therapies. However, relatively few kinase inhibitors have been identified to date and so effort is being made to discover new molecules that interact with kinases. A number of kinase inhibitors such as Gefitinib (Approved for Non-Small Cell Lung cancer) have shown promise in clinical trials against prostate cancer. Most of the other kinase inhibitors in clinical trial (3 in Phase III) against prostate cancer targets kinases that inhibits angiogenesis. Tumor angiogenesis is the formation of new blood vessels which supplies cancer cells with nutrients and oxygen. Antiangiogenic agents work by cutting off blood supply to tumors thus to starving cancer cells to death.
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. Tyrosine kinase functions as an “on” or “off” switch in many cellular functions. It can become mutated, stuck in the “on” position, and cause unregulated growth of the cell, which is a necessary step for the development of prostate cancer. Numerous tyrosine kinase inhibitors have proven to be effective anti-tumor agents and anti-leukemic agents. For example, in chronic myelogenous leukemia, the Abelson tyrosine kinase inhibitor Imatinib (Gleevec™) targets the activity of BCR-ABL oncoprotein; in acute promyelocytic leukemia (APL), all-trans-retinoic acid (ATRA) or arsenic trioxide (As2O3) targets PML-RARα fusion. The introduction of ATRA or Imatinib in the treatment of APL or chronic myelogenous leukemia patients has significantly improved the management of these diseases.
An effective tyrosine kinase inhibitor must be capable of killing or incapacitating prostate cancer cells without causing excessive damage to normal cells. Elevated levels of LIMK1 kinase are expressed in prostate cancer, a kinase which itself is activated by MRCKα. Inhibitors of the MRCKα kinase may restore normal cell proliferation and provide a key solution to cancer treatment. Medicinal plants have been one of the major sources for the discovery of a number of current clinically used anticancer drugs.
Jamaica is known for its rich biodiversity and its abundant usage of medicinal plants as ethno medicines. Tillandsia recurvata L. (Bromeliaceae) which is commonly called the Jamaican Ball Moss or the Old Man's beard is one of the several important plants found in Jamaica. Several countries report its use in their ethnomedicine. The major reported use is in Brazil where the plant is used against rheumatism, ulcers and hemorrhoids. Previous phytochemical studies showed the presence of; five hydroperoxyclycloartanes, a dicinnamate, a flavanone and a caffeic acid ester from the whole plant extracts.
In his U.S. Pat. No. 7,713,556 issued May 11, 2010, one of the inventors named herein investigated the anti-tumor and anti-inflammatory properties of a silica acid moiety extract of Jamaican Ball Moss.
The present inventors have found that a class of cycloartane isolates from the indigenous plant selectively inhibits MRCKα kinase and angiogenesis of (growth of new blood vessels) to reduce the viability of prostate cancer cells. The extract holds promise as a chemopreventive agent.